Sibutramine is a neuronal monoamine reuptake inhibitor, which has the chemical name [N-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine. Originally disclosed in U.S. Pat. Nos. 4,746,680 and 4,806,570, sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, e.g., Buckett et al., Prog. Neuro-psychopharm. & Biol. Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm., 26:607-611 (1989).
Racemic sibutramine is sold as a hydrochloride monohydrate under the trade name MERIDIA®, and is indicated for the treatment of obesity. Physician's Desk Reference® 1509-1513 (54th ed., 2000). The treatment of obesity using racemic sibutramine is disclosed, for example, in U.S. Pat. No. 5,436,272.
Sibutramine is rapidly absorbed from the gastrointestinal tract following oral administration and undergoes an extensive first-pass metabolism that yields the metabolites desmethylsibutramine (“DMS”) and didesmethylsibutramine (“DDMS”), as shown below in Scheme I. 
Both didesmethylsibutramine and desmethylsibutramine have interesting and useful biological properties. Each of these sibutramine metabolites can exist as an enantiomeric pair of R and S enantiomers, as shown below in Scheme II, which also exhibit interesting and useful biological properties: 
Until now, the preparation of racemic desmethylsibutramine and didesmethylsibutramine has been inefficient. Consequently, a need exists for improved methods of their synthesis. A particular need exists for the preparation of enantiomerically pure metabolites of sibutramine and derivatives thereof.